Many strains of mice are susceptible to acute infection with Leishmania donovani, although most strains develop protective Th-l type responses and eventually control visceral parasites. Still, strains of mice that exhibit similar patterns of acute susceptibility to infection may heal at dramatically different rates as evidenced by the fact that C57BL/6 mice exerting rapid control of visceral parasites while BALB/c mice develop persistent infections. We have shown that both BALB/c and C57BL/6 mice which lack the gene for IL-10 are highly resistant to acute infection and that both strains of IL-10 deficient mice rapidly eliminate visceral parasites. These studies implicate IL-10 as an important cytokine that regulates the development of resistance during visceral disease. In addition, we have observed that mice lacking the gene for the co-stimulatory molecule, CD28, are also highly resistant to infection with L. donovani. However, in contrast to IL-10 deficient mice, resistance in CD28 deficient mice cannot be linked to a heightened immune response. Instead, we believe that these mice may be deficient in factors or stimuli required for parasite growth in visceral tissues. In this proposal, we will focus on how the presence or absence of IL-10 production by parasitized macrophages alters macrophage microbicidal function and ask whether IL-10 plays a critical role in regulating the production of pro-inflammatory cytokines such as IL-12, IFN-gamma and TNF-alpha, which are critical to the development of a protective Thl type response. We will also examine whether a failure to produce anti-inflammatory factors such as IL-10 or TGF-beta is the basis for resistance in CD28 deficient mice and whether deficiencies in antibody production in these mice is linked to cytokine production and disease progression.